Process for the preparation of benzonorbornenes

Abstract

The present invention relates to a novel process for the preparation of 9-dichloromethylene-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-ylamine which process comprises a) reacting cyclopentadiene in the presence of a radical initiator and CXCl.sub.3, wherein X is chloro or bromo, to a compound of formula II ##STR00001## aa) reacting cyclopentadiene with CXCl.sub.3, wherein X is chloro, in the presence of a metal catalyst to a compound of formula II ##STR00002## wherein X is chloro, b) reacting the compound of formula II with a base in the presence of an appropriate solvent to the compound of formula III ##STR00003## c) and converting the compound of formula III in the presence of 1,2-dehydro-6-nitrobenzene to the compound of formula IV ##STR00004## and d) hydrogenating the compound of formula IV in the presence of a metal catalyst.

Claims

1. A process for the preparation of the compound of formula III ##STR00034## which process comprises a) reacting cyclopentadiene with CXCl.sub.3, wherein X is chloro or bromo, in the presence of a radical initiator to produce a compound of formula II ##STR00035## wherein X is chloro or bromo, and wherein the radical initiator is selected from at least one of methyl ethyl ketone peroxide, benzoyl peroxide, azobisisobutyronitrile, dibenzoylperoxide, bis(tert-butylcyclohexyl)peroxydicarbonate, a metal salt, and a metal salt complex, and b) reacting the compound of formula II with a base in the presence of an appropriate solvent.

2. A process according to claim 1, wherein X is bromo.

3. The process according to claim 1, wherein the radical initiator is selected from at least one of azobisisobutyronitrile, dibenzoylperoxide and bis(tert-butylcyclohexyl)peroxydicarbonate.

4. The process according to claim 1, wherein the radical initiator is azobisisobutyronitrile.

Description

PREPARATORY EXAMPLES

Example P1: Preparation of the Compound of Formula IIa

(1) ##STR00025##

(2) Azobisisobutyronitrile (2.5 g) was dissolved in bromotrichloromethane (250 g). Bromotrichloromethane (650 g) was loaded into a glass reactor under inert atmosphere (nitrogen) and heated to 85° C. ⅓ of the azobisisobutyronitrile solution (84 g) was added into the reactor at once and the reactor content was heated again to 85° C. followed by simultaneous addition of the remaining ⅔ of azobisisobutyronitrile solution (168.5 g) and a mixture of cyclopentadiene (100 g, freshly distilled) and methylcyclohexane (10 g) during 2.5 hours at 85° C. The reaction mixture was stirred for an additional 1 hour at 85° C., and then cooled to ambient temperature. Large amount of solvent (bromotrichloromethane) was evaporated in vacuum (60.fwdarw.70° C., 15.fwdarw.50 mbar). Methylcyclohexane (50 g) was added to the distillation residue and the distillation was continued (60.fwdarw.70° C., 15.fwdarw.15 mbar). The crude product (distillation residue) was dried in vacuum for an additional 30 min (70° C., 15 mbar). Yield 389 g of the compound of formula IIa in form of a brown oil, 94% pure, 92% yield, mixture of regioisomers.

Example P2: Preparation of the Compound of Formula III

(3) ##STR00026##

(4) A glass reactor was loaded with bromo(trichloromethyl)cyclopentene (27.83 g, compound IIa), methylcyclohexane (62 mL), methyl-tert-butylether (62 mL) and bis(2-methoxyethyl) ether (diglyme, 6.7 g) under inert atmosphere (nitrogen). The mixture was cooled to −10° C. in an ice/NaCl bath. Sodium tert-butoxide (20.3 g) was added into the reactor as solid during 10 min while keeping the temperature below +5° C. When the addition was done, the reaction mixture was stirred at 0-5° C. for 2 hours. The reaction mixture was quenched with a mixture of ice-cold water (80 mL) and ice (40 g) and then the pH value of the water phase was adjusted to with 32% HCl (ca. 3 mL). The water phase was separated and the organic phase was dried over anhydrous potassium carbonate at 0° C. The potassium carbonate was filtered off and rinsed with methyl-tert-butylether (10 mL). Methyl ethyl ketone (10 g) was added to the combined filtrate as internal standard and the concentration of 6,6-dichlorofulvene (compound of formula III) was determined by .sup.1H NMR spectroscopy. Yield 81% [9.7 g of 9.9% (ca. 0.53 M) solution]. The solution was stored in a freezer and then used for the next step.

Example P3: Preparation of the Compound of Formula IV

(5) ##STR00027##

(6) A cold solution of 6,6-dichlorofulvene obtained in the previous step (9% in methyl-tert-butylether/methylcyclohexane=1:1) was placed in a glass reactor and heated quickly to 35° C. tert-pentyl nitrite (2.66 g) was added into the reactor followed by simultaneous addition of tert-pentyl nitrite (9.46 g) and a solution of 6-nitroanthranilic acid (11.6 g, 96.6%) in methyl ethyl ketone (42 mL) during 80 minutes at a temperature of 35° C. The reaction mixture was stirred for additional 30 min at the same temperature and then all the volatiles were removed by rotary evaporation. The remaining residue was crystallized from methanol (20 mL) at +5° C. for 15 hours. The brown crystalline material was filtered, washed with cold methanol (15 mL) and dried in air. Yield 7.10 g (42%, 98% pure product).

Example P4: Hydrogenation of the Compound of Formula IV

(7) An autoclave was charged with THF (130 ml), wet Raney-Nickel (2 g) and compound of formula IV (20 g). The autoclave was closed, the content started to agitate, purged three times with nitrogen to remove oxygen and then three times with hydrogen. The reactor was pressurized with hydrogen to 5 bar. Then the content of the autoclave was heated to 40° C., maintaining pressure with additional hydrogen as needed. When hydrogen uptake stopped, typically after 3-4 h, the reaction mass was held another 30 min at 40° C. After this time, the pressure was released and the content was cooled to ambient temperature. The solvent was removed under vacuum and the resulting oil crystallized upon standing to yield 18 g of the yellowish to brownish compound of formula I (96%, 94% pure product).

Example P5: Preparation of CTCM-Cyclopentene of Formula IIa Using Grubbs-I Catalyst

(8) ##STR00028##

(9) A mixture of cyclopentadiene (2.0 g), azobisisobutyronitrile (0.5 g), benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (Grubbs' 1.sup.st Generation Catalyst, 12.2 mg, 0.05 mol %) and carbon tetrachloride (14 g) was heated at 75° C. under inert atmosphere (argon). The conversion was monitored by GC. After 4 hours the reaction was completed to produce chloro(trichloromethyl)cyclopentene as a mixture of three isomers in 85% yield (GC, dodecane was used as a standard).

Example P6: Preparation of CTCM-Cyclopentene of Formula IIa Using CuCl/TMEDA Catalyst

(10) ##STR00029##
Catalyst Solution:

(11) A mixture of copper (I) chloride (0.99 g), tetramethylethylenediamine (TMEDA, 2.32 g) and acetonitrile (100 mL) was heated at 75° C. for 25 min under nitrogen atmosphere and then cooled to room temperature.

(12) Cyclopentadiene Solution:

(13) Freshly prepared cyclopentadiene (66.0 g) was dissolved in carbon tetrachloride (307 g).

(14) Reaction:

(15) Under nitrogen atmosphere acetonitrile (80 g) and 40% of the catalyst solution were placed into a glass reactor under nitrogen. The mixture was heated to a temperature of 75° C. Then 40% of the cyclopentadiene solution was added into the reactor in one portion followed by simultaneous addition of the rests of the catalyst solution and the cyclopentadiene solution while keeping the temperature between 60 and 70° C. The cyclopentadiene solution was added in 1 hour and the catalyst solution in 1.5 hours. The reaction mixture was stirred for an additional 1 hour at 70° C., cooled to ambient temperature and filtered. The solvent was removed by rotary evaporation and the residue was fractionated by vacuum distillation (40-45° C., 0.1 mbar). Yield 170 g (75%, 97-98% purity), mixture of three regioisomers.

Example P7: Preparation of the Compound of Formula III

(16) ##STR00030##

(17) Sodium tert-butoxide (69.2 g) was stirred with chlorobenzene (175 ml) for 30 min at room temperature to produce a fine suspension.

(18) A glass reactor was loaded with chloro(trichloromethyl)cyclopentene (69.1 g), chlorobenzene (275 ml), and bis(2-methoxyethyl) ether (diglyme, 21.1 g) under inert atmosphere (nitrogen). The mixture was cooled to −20° C. and the suspension of sodium tert-butoxide was added into the reactor portion-wise over 35 min while keeping the temperature below +3° C. When the addition was done, the reaction mixture was stirred at −5° C. for 3 hours. The reaction mixture was quenched with a mixture of 0.5 M aqueous HCl solution (300 ml) and ice (200 g). The pH value of the water phase was controlled to be pH ≦2. The water phase was separated and the organic phase was extracted with the same mixture of water and ice two times (This was necessary for a complete removal of tert-butanol and diglyme). The concentration of 6,6-dichlorofulvene was determined by .sup.1H NMR spectroscopy using chlorobenzene (solvent) as an internal standard. Yield 75% [510 g of 6.8% (ca. 0.52 M) solution]. The solution was stored in a freezer or dry ice and then used for the next step. Comment: The yield just after the quench (no further extractions) was 85%. The solution was lost in the phase separations.

(19) A preferred benzonorbornene fungicide which can be advantageously prepared using the process according to the invention is 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (9-dichloromethylene-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl)-amide of formula V

(20) ##STR00031##

(21) The compound of formula V is described, for example, in WO 2007/048556. The compound of formula V can occur in two enantiomeric forms. The compound of formula Va

(22) ##STR00032##
which chemical designation is 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ((1S,4R)-9-dichloromethylene-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl)-amide, and the compound of formula Vb

(23) ##STR00033##
which chemical designation is 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ((1R,4S)-9-dichloromethylene-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl)-amide. The optical rotation angles [α].sup.23.5 are −119.26° and +119.23° (in tetrahydrofurane) respectively.